̽��ֱ�� of Cambridge - neurodegeneration

Glaucoma drug shows promise against neurodegenerative diseases, animal studies suggest

cjb250 — Thu, 31 Oct 2024 10:00:09 +0000

Researchers in the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge screened more than 1,400 clinically-approved drug compounds using zebrafish genetically engineered to make them mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors – of which the glaucoma drug methazolamide is one – clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Tauopathies are neurodegenerative diseases characterised by the build-up in the brain of tau protein ‘aggregates’ within nerve cells. These include forms of dementia, Pick's disease and progressive supranuclear palsy, where tau is believed to be the primary disease driver, and Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head trauma, as has been reported in football and rugby players), where tau build-up is one consequence of disease but results in degeneration of brain tissue.

There has been little progress in finding effective drugs to treat these conditions. One option is to repurpose existing drugs. However, drug screening – where compounds are tested against disease models – usually takes place in cell cultures, but these do not capture many of the characteristics of tau build-up in a living organism.

To work around this, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish grow to maturity and are able to breed within two to three months and produce large numbers of offspring. Using genetic manipulation, it is possible to mimic human diseases as many genes responsible for human diseases often have equivalents in the zebrafish.

In a study published today in Nature Chemical Biology, Professor David Rubinsztein, Dr Angeleen Fleming and colleagues modelled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for other diseases.

Dr Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, joint first author, said: “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms. They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice.”

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase – which is important for regulating acidity levels in cells – helped the cell rid itself of the tau protein build-up. It did this by causing the lysosomes – the ‘cell’s incinerators’ – to move to the surface of the cell, where they fused with the cell membrane and ‘spat out’ the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain, they found that those treated with the drug performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysis of the mouse brains showed that they indeed had fewer tau aggregates, and consequently a lesser reduction in brain cells, compared with the untreated mice.

Fellow joint author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were excited to see in our mouse studies that methazolamide reduces levels of tau in the brain and protects against its further build-up. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

Professor Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge, said: “Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. Although we’ve only looked at its effects in zebrafish and mice, so it is still early days, we at least know about this drug’s safety profile in patients. This will enable us to move to clinical trials much faster than we might normally expect if we were starting from scratch with an unknown drug compound.

“This shows how we can use zebrafish to test whether existing drugs might be repurposed to tackle different diseases, potentially speeding up significantly the drug discovery process.”

̽��ֱ��team hopes to test methazolamide on different disease models, including more common diseases characterised by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

̽��ֱ��research was supported by the UK Dementia Research Institute (through UK DRI Ltd, principally funded through the Medical Research Council), Tau Consortium and Wellcome.

Reference
Lopez, A & Siddiqi, FH et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; DOI: 10.1038/s41589-024-01762-7

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the build-up in the brain of the protein tau, which causes various forms of dementia and is implicated in Alzheimer’s disease.

Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms

Ana Lopez Ramirez

Kuznetsov_Peter

Zebrafish

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Cambridge joins forces with ARIA to fast-track radical new technologies to revolutionise brain health

Anonymous — Wed, 09 Oct 2024 12:57:22 +0000

̽��ֱ��collaboration, which includes researchers from the ̽��ֱ�� of Cambridge, aims to accelerate progress on new neuro-technologies, including miniaturised brain implants designed to treat depression, dementia, chronic pain, epilepsy and injuries to the nervous system.

Neurological and mental health disorders will affect four in every five people in their lifetimes, and present a greater overall health burden than cancer and cardiovascular disease combined. For example, 28 million people in the UK are living with chronic pain and 1.3 million people with traumatic brain injury.

Neuro-technology – where technology is used to control the nervous system - has the potential to deliver new treatments for these disorders, in much the same way that heart pacemakers, cochlear implants and spinal implants have transformed medicine in recent decades.

̽��ֱ��technology can be in the form of electronic brain implants that reset abnormal brain activity or help deliver targeted drugs more effectively, brain-computer interfaces that control prosthetic limbs, or technologies that train the patient’s own cells to fight disease. ARIA’s Scalable Neural Interfaces opportunity space is exploring ways to make the technology more precise, less invasive, and applicable to a broader range of diseases.

Currently, an implant can only interact with large groups of neurons, the cells that transmit information around the brain. Building devices that interact with single neurons will mean a more accurate treatment. Neuro-technologies also have the potential to treat autoimmune disorders, including rheumatoid arthritis, Crohn’s disease and type-1 diabetes.

̽��ֱ��science of building technology small enough, precise enough and cheap enough to make a global impact requires an environment where the best minds from across the UK can collaborate, dream up radical, risky ideas and test them without fear of failure.

Professor George Malliaras from the ̽��ֱ�� of Cambridge’s Department of Engineering is one of the project leaders. “Miniaturised devices have the potential to change the lives of millions of people currently suffering from neurological conditions and diseases where drugs have no effect,” he said. “But we are working at the very edge of what is possible in medicine, and it is hard to find the support and funding to try radical, new things. That is why the partnership with ARIA is so exhilarating, because it is giving brilliant people the tools to turn their original ideas into commercially viable devices that are cheap enough to have a global impact.”

Cambridge’s partnership with ARIA will create a home for original thinkers who are struggling to find the funding, space and mentoring needed to stress-test their radical ideas. ̽��ֱ��three-year partnership is made up of two programmes:

̽��ֱ��Fellowship Programme (up to 18 fellowships)

Blue Sky Fellows – a UK-wide offer - we will search the UK for people from any background, with a radical idea in this field and the plan and personal skills to develop it. ̽��ֱ��best people will be offered a fellowship with the funding to test their ideas in Cambridge rapidly. These Blue Sky Fellows will receive mentorship from our best medical, scientific and business experts and potentially be offered accommodation at a Cambridge college. We will be looking for a specific type of person to be a Blue Sky Fellow. They must be the kind of character who thinks at the very edge of the possible, who doesn’t fear failure, and whose ideas have the potential to change billions of lives, yet would struggle to find funding from existing sources. Not people who think outside the box, more people who don’t see a box at all.

Activator Fellows - a UK-wide offer - those who have already proved that their idea can work, yet need support to turn it into a business, will be invited to become Activator Fellows. They will be offered training in entrepreneurial skills including grant writing, IP management and clinical validation, so their innovation can be ready for investment.

̽��ֱ��Ecosystem Programme

̽��ֱ��Ecosystem Programme is about creating a vibrant, UK-wide neurotechnology community where leaders from business, science, engineering, academia and the NHS can meet, spark ideas and form collaborations. This will involve quarterly events in Cambridge, road trip events across the UK and access to the thriving online Cambridge network, Connect: Health Tech.

“This unique partnership is all about turning radical ideas into practical, low-cost solutions that change lives,” said Kristin-Anne Rutter, Executive Director of Cambridge ̽��ֱ�� Health Partners. “Cambridge is fielding its best team to make this work and using its networks to bring in the best people from all over the UK. From brilliant scientists to world-leading institutes, hospitals and business experts, everyone in this collaboration is committed to the ARIA partnership because, by working together, we all see an unprecedented opportunity to make a real difference in the world.”

“Physical and mental illnesses and diseases that affect the brain such as dementia are some of the biggest challenges we face both as individuals and as a society,” said Dr Ben Underwood, Associate Professor of Psychiatry at the ̽��ֱ�� of Cambridge and Honorary Consultant Psychiatrist at Cambridgeshire and Peterborough NHS Foundation Trust. “This funding will bring together different experts doing things at the very limits of science and developing new technology to improve healthcare. We hope this new partnership with the NHS will lead to better care and treatment for people experiencing health conditions.”

Cambridge partners in the project include the Departments of Engineering and Psychiatry, Cambridge Neuroscience, the Milner Therapeutics Institute, the Maxwell Centre, Cambridge ̽��ֱ�� Health Partners (CUHP), Cambridge Network, the Babraham Research Campus, Cambridgeshire and Peterborough NHS Foundation Trust, and Vellos.

A team from across the Cambridge life sciences, technology and business worlds has announced a multi-million-pound, three-year collaboration with the Advanced Research and Invention Agency (ARIA), the UK government’s new research funding agency.

Science Photo Library via Getty Images

Illustration of human brain

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AI speeds up drug design for Parkinson’s ten-fold

sc604 — Wed, 17 Apr 2024 09:00:00 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, designed and used an AI-based strategy to identify compounds that block the clumping, or aggregation, of alpha-synuclein, the protein that characterises Parkinson’s.

̽��ֱ��team used machine learning techniques to quickly screen a chemical library containing millions of entries, and identified five highly potent compounds for further investigation.

Parkinson’s affects more than six million people worldwide, with that number projected to triple by 2040. No disease-modifying treatments for the condition are currently available. ̽��ֱ��process of screening large chemical libraries for drug candidates – which needs to happen well before potential treatments can be tested on patients – is enormously time-consuming and expensive, and often unsuccessful.

Using machine learning, the researchers were able to speed up the initial screening process ten-fold, and reduce the cost by a thousand-fold, which could mean that potential treatments for Parkinson’s reach patients much faster. ̽��ֱ��results are reported in the journal Nature Chemical Biology.

Parkinson’s is the fastest-growing neurological condition worldwide. In the UK, one in 37 people alive today will be diagnosed with Parkinson’s in their lifetime. In addition to motor symptoms, Parkinson’s can also affect the gastrointestinal system, nervous system, sleeping patterns, mood and cognition, and can contribute to a reduced quality of life and significant disability.

Proteins are responsible for important cell processes, but when people have Parkinson’s, these proteins go rogue and cause the death of nerve cells. When proteins misfold, they can form abnormal clusters called Lewy bodies, which build up within brain cells stopping them from functioning properly.

“One route to search for potential treatments for Parkinson’s requires the identification of small molecules that can inhibit the aggregation of alpha-synuclein, which is a protein closely associated with the disease,” said Professor Michele Vendruscolo from the Yusuf Hamied Department of Chemistry, who led the research. “But this is an extremely time-consuming process – just identifying a lead candidate for further testing can take months or even years.”

While there are currently clinical trials for Parkinson’s currently underway, no disease-modifying drug has been approved, reflecting the inability to directly target the molecular species that cause the disease.

This has been a major obstacle in Parkinson’s research, because of the lack of methods to identify the correct molecular targets and engage with them. This technological gap has severely hampered the development of effective treatments.

̽��ֱ��Cambridge team developed a machine learning method in which chemical libraries containing millions of compounds are screened to identify small molecules that bind to the amyloid aggregates and block their proliferation.

A small number of top-ranking compounds were then tested experimentally to select the most potent inhibitors of aggregation. ̽��ֱ��information gained from these experimental assays was fed back into the machine learning model in an iterative manner, so that after a few iterations, highly potent compounds were identified.

“Instead of screening experimentally, we screen computationally,” said Vendruscolo, who is co-Director of the Centre for Misfolding Diseases. “By using the knowledge we gained from the initial screening with our machine learning model, we were able to train the model to identify the specific regions on these small molecules responsible for binding, then we can re-screen and find more potent molecules.”

Using this method, the Cambridge team developed compounds to target pockets on the surfaces of the aggregates, which are responsible for the exponential proliferation of the aggregates themselves. These compounds are hundreds of times more potent, and far cheaper to develop, than previously reported ones.

“Machine learning is having a real impact on drug discovery – it’s speeding up the whole process of identifying the most promising candidates,” said Vendruscolo. “For us, this means we can start work on multiple drug discovery programmes – instead of just one. So much is possible due to the massive reduction in both time and cost – it’s an exciting time.”

̽��ֱ��research was conducted in the Chemistry of Health Laboratory in Cambridge, which was established with the support of the UK Research Partnership Investment Fund (UKRPIF) to promote the translation of academic research into clinical programmes.

Reference:
Robert I Horne et al. ‘Discovery of Potent Inhibitors of α-Synuclein Aggregation Using Structure-Based Iterative Learning.’ Nature Chemical Biology (2024). DOI: 10.1038/s41589-024-01580-x

Researchers have used artificial intelligence techniques to massively accelerate the search for Parkinson’s disease treatments.

Machine learning is having a real impact on drug discovery – it’s speeding up the whole process of identifying the most promising candidates

Michele Vendruscolo

Nathan Pitt

Michele Vendruscolo

Yes

Clinical trial underway to treat ultra-rare genetic disease with possible link to leader of mutiny on the Bounty

jg533 — Thu, 21 Mar 2024 09:00:00 +0000

A clinical trial to look at repurposing the UK-licensed medicine deferiprone for patients with the ultra-rare genetic disease neuroferritinopathy has launched today at the ̽��ֱ�� of Cambridge.

Neuroferritinopathy is a progressive and incurable brain disorder caused by changes in a gene that produces a specific protein - ferritin light chain protein. This change leads to the build-up of iron in the brain. ̽��ֱ��disease usually appears in middle-aged adults and causes severe symptoms that impact on day-to-day life, eventually resulting in the loss of speech and swallowing. There are currently no effective treatments.

Funded by LifeArc, the new randomised placebo-controlled trial - DefINe - will be led by Professor Patrick Chinnery from the Department of Clinical Neurosciences. It aims to stop the progression of the disease by reducing the iron accumulation in the brain with an existing drug called deferiprone. Deferiprone is an affordable oral tablet that is already licensed for use in the UK to reduce iron levels in blood conditions like thalassemia. If successful, the trial could also open the possibility of deferiprone being used for other neurodegenerative conditions linked with build-up of iron the brain.

Professor Chinnery said: “Neuroferritinopathy leads to severe disability and currently has no cure. ̽��ֱ��DefINe trial will show whether we can stop the disease in its tracks by pulling iron out of the brain using a well-known medicine called deferiprone.

“By funding this study, LifeArc has given the first hope of a treatment for affected families. If successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the build-up of iron in the brain, including Parkinson’s disease.”

Neuroferritinopathy affects approximately 100 patients worldwide. Initial discovery of the condition came when a surprising number of individuals diagnosed found to live in the Lake District in Cumbria experienced similar symptoms with a series of incorrect diagnoses. Research into the ancestry of these families by Professor John Burn, a clinical geneticist at Newcastle Hospitals NHS Foundation Trust, discovered the genetic commonality and also found an interesting potential link to the past.

Professor Burn found that a rare mutation caused the progression of the condition and almost all the known cases were likely to be descended from the same ancestor. He traced it back to the 18th Century in Cockermouth in Cumbria and families with the surname Fletcher. Professor Burn suggested they could have shared common ancestry with Fletcher Christian (Fletcher being his surname), known for leading the mutiny on the Bounty in April 1789, given he was also from the region.

̽��ֱ��DefINe trial will involve 40 patients taking the drug for a year, who will undergo state-of-the-art 7T magnetic resonance imaging (MRI) scanning to monitor the iron levels in the brain throughout. ̽��ֱ��evidence collected will form the basis of an application for licensing in the UK under ‘Exceptional Circumstances’, which is often used for rare conditions where the number of people affected is low. This means, if the trial is successful the drug could go on to benefit all people with the condition more quickly.

Samantha Denison, a patient hoping to participate in the trial, said: “It came as such a surprise to be informed of the trial and to learn that we have not been forgotten about. To have the chance to be involved in the trial gives me such hope. If it can help to slow or stop the condition progressing, that would be a huge relief. Just to know that by taking part we could also be helping future generations, is amazing.”

LifeArc has contributed £750,000 to the project and Lipomed, a Swiss life sciences company, has offered to provide both a cost-effective generic form of deferiprone, Deferiprone Lipomed, and a placebo to the trial – a Gift in Kind worth £250,000.

Dr Catriona Crombie, Head of LifeArc’s Rare Disease Translational Challenge, said: “Drug repurposing trials like this are an increasingly effective way of taking treatments that have already been approved and applying them to new conditions and diseases. This will help unlock new treatments for conditions that currently have few, if any, available."

Dr Chantal Manz, Chief Scientific Officer Lipomed AG, Switzerland, said: “Lipomed is very excited to support this promising study concept in patients with neuroferritinopathy, by providing deferiprone 500 mg film-coated tablets and matching placebo tablets. We recognise the unmet clinical need and the potentially significant benefit of this orally active iron chelator. Deferiprone is able to penetrate the blood-brain barrier and may reduce cerebral iron accumulation in patients with this extremely rare, but devastating genetic neurodegenerative disorder, for which no alternative treatments are available.”

Adapted from a press release by LifeArc.

If successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the build-up of iron in the brain, including Parkinson’s disease.

Patrick Chinnery

Patrick Chinnery looks at brain scans

Yes

Scientists identify genes linked to DNA damage and human disease

cjb250 — Fri, 16 Feb 2024 10:17:07 +0000

̽��ֱ��work, published in Nature, provides insights into cancer progression and neurodegenerative diseases as well as a potential therapeutic avenue in the form of a protein inhibitor.

̽��ֱ��genome contains all the genes and genetic material within an organism's cells. When the genome is stable, cells can accurately replicate and divide, passing on correct genetic information to the next generation of cells. Despite its significance, little is understood about the genetic factors governing genome stability, protection, repair, and the prevention of DNA damage.

In this new study, researchers from the UK Dementia Research Institute, at the ̽��ֱ�� of Cambridge, and the Wellcome Sanger Institute set out to better understand the biology of cellular health and identify genes key to maintaining genome stability.

Using a set of genetically modified mouse lines, the team identified 145 genes that play key roles in either increasing or decreasing the formation of abnormal micronuclei structures. These structures indicate genomic instability and DNA damage, and are common hallmarks of ageing and diseases.

̽��ֱ��most dramatic increases in genomic instability were seen when the researchers knocked out the gene DSCC1, increasing abnormal micronuclei formation five-fold. Mice lacking this gene mirrored characteristics akin to human patients with a number of rare genetic disorders, further emphasising the relevance of this research to human health.

Using CRISPR screening, researchers showed this effect triggered by DSCC1 loss could be partially reversed through inhibiting protein SIRT1. This offers a highly promising avenue for the development of new therapies.

̽��ֱ��findings help shed light on genetic factors influencing the health of human genomes over a lifespan and disease development.

Professor Gabriel Balmus, senior author of the study at the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, formerly at the Wellcome Sanger Institute, said: “Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes, with the goal of improving outcomes and the overall quality of life for individuals across various conditions.”

Dr David Adams, first author of the study at the Wellcome Sanger Institute, said: “Genomic stability is central to the health of cells, influencing a spectrum of diseases from cancer to neurodegeneration, yet this has been a relatively underexplored area of research. This work, of 15 years in the making, exemplifies what can be learned from large-scale, unbiased genetic screening. ̽��ֱ��145 identified genes, especially those tied to human disease, offer promising targets for developing new therapies for genome instability-driven diseases like cancer and neurodevelopmental disorders.”

This research was supported by Wellcome and the UK Dementia Research Institute.

Reference
Adams, DJ et al. Genetic determinants of micronucleus formation in vivo. Nature; 14 Feb 2024; DOI: 10.1038/s41586-023-07009-0

Adapted from a press release from the Wellcome Sanger Institute.

Cambridge scientists have identified more than one hundred key genes linked to DNA damage through systematic screening of nearly 1,000 genetically modified mouse lines.

Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes

Gabriel Balmus

qimono

DNA puzzle

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Ageing: can we add more life to our years?

jg533 — Wed, 20 Dec 2023 08:59:28 +0000

Research advances at the ̽��ֱ�� of Cambridge mean that the eternal quest to reverse the march of time may soon become a reality.

AI-driven techniques reveal new targets for drug discovery

Anonymous — Wed, 27 Sep 2023 14:17:57 +0000

̽��ֱ��research team, led by the ̽��ֱ�� of Cambridge, presented an approach to identify therapeutic targets for human diseases associated with a phenomenon known as protein phase separation, a recently discovered phenomenon widely present in cells that drives a variety of important biological functions.

Protein phase separation at the wrong place or time could disrupt key cellular functions or create aggregates of molecules linked to neurodegenerative diseases. It is believed that poorly formed cellular condensates could contribute to cancers and might help explain the aging process.

̽��ֱ��Cambridge researchers, working in collaboration with generative artificial intelligence (AI)-driven drug discovery company Insilico Medicine, developed a method for finding new targets for drug discovery in diseases caused by dysregulation of the protein phase separation process. ̽��ֱ��team found that they could replicate disease characteristics in cells by controlling the behaviour of these targets. Their results are reported in the Proceedings of the National Academy of Sciences (PNAS).

“ ̽��ֱ��discovery of protein phase separation opens up new opportunities for drug discovery,” said Professor Michele Vendruscolo from Cambridge’s Yusuf Hamied Department of Chemistry, who led the research. “However, it has been unclear which proteins undergo this process and represent the best targets for effective pharmacological interventions.”

In the study, researchers combined Insilico’s proprietary target identification engine PandaOmics with the FuzDrop method to identify disease-associated proteins prone to phase separation. PandaOmics is an AI-driven therapeutic target discovery tool that integrates multiple omics and text AI bioinformatics models to assess the potential of proteins as therapeutic targets.

FuzDrop is a tool introduced by the Cambridge team, which calculates the propensity of a protein to undergo spontaneous phase separation, aiding in the identification of proteins prone to form liquid-liquid phase-separated condensates.

Using this approach, the researchers conducted a large-scale study of human sample data, quantified the relative impact of protein phase separation in regulating various pathological processes associated with human disease, prioritised candidates with high PandaOmics and FuzDrop scores and generated a list of possible therapeutic targets for human diseases linked with protein phase separation.

̽��ֱ��researchers validated the differential phase separation behaviours of three predicted Alzheimer’s disease targets (MARCKS, CAMKK2 and p62) in two cell models of Alzheimer’s disease, which provides experimental validation for the involvement of these predicted targets in Alzheimer's disease and support their potential as therapeutic targets. By modulating the formation and behaviour of these condensates, it may be possible to develop new interventions to mitigate the pathological processes associated with Alzheimer's disease.

“It has been challenging so far to understand the role of protein phase separation in cellular functions,” said Vendruscolo. “Even more difficult has been to clarify the exact nature of its association with human disease. By working with Insilico Medicine, we have developed an approach to systematically address this problem and identify a variety of possible therapeutic targets. We have thus provided a roadmap for researchers to navigate this complex terrain.”

“We are pleased to reach the milestones of our collaboration with the ̽��ֱ�� of Cambridge,” said Frank Pun, PhD, head of Insilico Medicine Hongkong, and co-author of the paper. “ ̽��ֱ��study is intended to provide initial directions for targeting disease-associated proteins prone to phase separation. With ongoing technical advancements in studying the protein phase separation process, coupled with the growing data about its roles in both cellular function and dysfunction, it is now possible to comprehend the causal relationship between these targets and diseases. We anticipate facilitating the translation of this preclinical research into novel therapeutic interventions soon.”

Reference:
Christine M. Lim et al. ‘Multiomic prediction of therapeutic targets for human diseases associated with protein phase separation.’ Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2300215120

Adapted from an Insilico Medicine press release.

Researchers have developed a method to identify new targets for human disease, including neurodegenerative conditions such as Alzheimer’s disease.

̽��ֱ��discovery of protein phase separation opens up new opportunities for drug discovery

Michele Vendruscolo

Juan Gaertner/Science Photo Library via Getty Images

Alzheimers disease. Computer illustration of amyloid plaques amongst neurons.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Slow-moving shell of water can make Parkinson’s proteins ‘stickier’

sc604 — Tue, 15 Nov 2022 14:32:31 +0000

When attempting to discover potential treatments for protein misfolding diseases, researchers have primarily focused on the structure of the proteins themselves. However, researchers led by the ̽��ֱ�� of Cambridge have shown that a thin shell of water is key to whether a protein begins to clump together, or aggregate, forming the toxic clusters which eventually kill brain cells.

Using a technique known as Terahertz spectroscopy, the researchers have shown that the movement of the water-based shell surrounding a protein can determine whether that protein aggregates or not. When the shell moves slowly, proteins are more likely to aggregate, and when the shell moves quickly, proteins are less likely to aggregate. ̽��ֱ��rate of movement of the shell is altered in the presence of certain ions, such as salt molecules, which are commonly used in the buffer solutions used to test new drug candidates.

̽��ֱ��significance of the water shell, known as the hydration or solvation shell, in the folding and function of proteins has been strongly disputed in the past. This is the first time the solvation shell has been shown to play a key role in protein misfolding and aggregation, which could have profound implications in the search for treatments. ̽��ֱ��results are reported in the journal Angewandte Chemie International.

When developing potential treatments for protein misfolding diseases such as Parkinson’s and Alzheimer’s disease, researchers have been studying compounds which can prevent the aggregation of key proteins: alpha-synuclein for Parkinson’s disease or amyloid-beta for Alzheimer’s disease. To date however, there are no effective treatments for either condition, which affect millions worldwide.

“It’s the amino acids that determine the final structure of a protein, but when it comes to aggregation, the role of the solvation shell, which sits on the outside of a protein, has been overlooked until now,” said Professor Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology, who led the research. “We wanted to know whether this water shell plays a role in protein behaviour – it’s been a question in the field for a while, but no one has been able to prove it.”

̽��ֱ��solvation shell slides around on the surface of the protein, acting like a lubricant. “We wondered whether, if the movement of water molecules was slower in the solvation shell of a protein, it could slow the movement of the protein itself,” said Dr Amberley Stephens, the paper’s first author.

To test the role of the solvation shell in the aggregation of proteins, the researchers used alpha-synuclein, the key protein implicated in Parkinson’s disease. Using Teraheartz spectroscopy, a powerful technique to study the behaviour of water molecules, they were able to observe the movement of the water molecules that surround the alpha-synuclein protein.

They then added two different salts in solution to the proteins: sodium chloride (NaCl), or regular table salt, and cesium iodide (CsI). ̽��ֱ��ions in the sodium chloride – Na+ and Cl- – bind strongly to the hydrogen and oxygen ions in water, while the ions in the cesium iodide make much weaker bonds.

̽��ֱ��researchers found that when the sodium chloride was added, the strong hydrogen bonds caused the movement of the water molecules in the solvation shell to slow down. This resulted in slower movement of the alpha-synuclein, and the aggregation rate increased. Conversely, when the cesium iodide was added, the water molecules sped up, and the aggregation rate decreased.

“In essence, when the water shell slows down, the proteins have more time to interact with each other, so they’re more likely to aggregate,” said Kaminski Schierle. “And on the flip side, when the solvation shell moves more quickly, the proteins become harder to catch, so they’re less likely to aggregate.”

“When researchers are screening for an aggregation inhibitor for Parkinson’s disease, they will usually use a buffer composition, but there’s been very little thought on how that buffer is interacting with the protein itself,” said Stephens. “Our results show that you need to understand the composition of the solvent inside the cell in order to mimic the conditions you have in the brain and ultimately end up with an inhibitor that works.”

“It’s so important to look at the whole picture, and that hasn’t been happening,” said Kaminski Schierle. “To effectively test whether a drug candidate will work in a patient, you need to mimic cellular conditions, which means you need to take everything into consideration, like salts and pH levels. ̽��ֱ��failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease.”

̽��ֱ��research was supported in part by Wellcome, Alzheimer’s Research UK, the Michael J Fox Foundation, and the Medical Research Council (MRC), part of UK Research and Innovation (UKRI). Gabriele Kaminski Schierle is a Fellow of Robinson College, Cambridge.

Reference:
Amberley D Stephens et al. ‘Decreased Water Mobility Contributes to Increased α-Synuclein Aggregation.’ Angewandte Chemie International (2022). DOI: 10.1002/anie.202212063

Water – which makes up the majority of every cell in the body – plays a key role in how proteins, including those associated with Parkinson’s disease, fold, misfold, or clump together, according to a new study.

̽��ֱ��failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease

Gabriele Kaminski Schierle

Sherbrooke Connectivity Imaging Lab via Getty

Corpus callosum, left-right connections, in a Parkinson's brain

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